Interferon-alpha (IFN-alpha) treatment results in long-term remissions in only 25%-40% of patients with chronic hepatitis B virus (HBV) infection. Famciclovir, the oral prodrug of penciclovir, inhibits HBV DNA replication. Five adults with chronic HBV infection in whom previous IFN-alpha therapy had failed were treated in a pilot study of overlapping IFN-alpha and famciclovir therapy totaling 20 weeks. HBV DNA levels decreased by 0.9 log units during the initial 4-week period of famciclovir alone, followed by a further decrease of 1.8 logs during the middle 12-week period of combination therapy. HBV DNA rose by 0.9 log during the final 4-week period of IFN-alpha alone. Two patients cleared HBV DNA, and their liver disease improved by clinical and histologic criteria. The combination of famciclovir and IFN-alpha appeared to be at least additive in suppressing HBV DNA. Efficacy trials of combination therapy with famciclovir and IFN-alpha are warranted.